Interactions between warfarin and three commonly prescribed fluoroquinolones

Carroll D N, Carroll D G

CRD summary

This review evaluated a potential increased anticoagulant response during concomitant therapy of warfarin and three commonly prescribed fluoroquinolones. Due to inconsistent findings, the authors concluded that there was insufficient evidence to support a potential increased anticoagulant response. The authors' conclusions were appropriate, but should be considered in the context of the review's methodological weaknesses.

Authors' objectives

To critically assess a potential increased anticoagulant response during concomitant therapy of warfarin and any of the three commonly prescribed fluoroquinolone antibiotics.

Searching

MEDLINE/PubMed and International Pharmaceutical Abstracts were searched from inception to January 2008. Search terms were reported. In addition, reference lists of retrieved articles were examined for additional studies. Searches were restricted to studies published in the English language.

Study selection

Studies of any design in human subjects following prescription of fluoroquinolones (ciprofloxacin, levofloxacin and moxifloxacin) for active indications for a minimum of three days planned administration were eligible for inclusion. Studies needed to report either pro-thrombin time or international normalised ratio values. Only studies published in English were included.

Included patients had various comorbidities. Mean ages ranged from 48 years to 85 years; more than three-quarters of all patients were over 60 years of age. Almost all patients had documented stable anticoagulation parameters prior to receiving a fluoroquinolone. The use of ciprofloxacin was reported in 11 studies, levofloxacin in seven studies and moxifloxacin in three studies. One study reported the use of levofloxacin or gatifloxacin. Reported outcomes included mean international normalised ratio change, mean pro-thrombin time change (seconds), mean maximum pro-thrombin time (seconds), time to discovery of enhanced anticoagulation (days) and bleeding complications.

The authors stated neither how the papers were selected for the review nor how many reviewers performed the selection.

Assessment of study quality

The authors did not state that they assessed validity.

Data extraction

The authors stated neither how the data were extracted for the review nor how many reviewers preformed the data extraction.

Methods of synthesis

Studies were combined narratively and grouped by fluoroquinolone.

Results of the review

Two randomised placebo controlled trials (n=41), two prospective open label trials (n=27), two retrospective cohort studies (n=49), one retrospective study (n=92) and 16 case reports or case series (n=96) were included in the review. Overall, studies showed inconsistent findings. Changes in pro-thrombin time and international normalised ratio values varied greatly from clinically insignificant mean changes (six studies: four prospective and two retrospective cohort) to values above the optimal therapeutic range. For ciprofloxacin or levofloxacin the increases were apparent at day five or six whereas these were identified earlier (at around three days) for moxifloxacin. Increased anticoagulation did not always result in bleeding complications. Overall, bleeding events occurred in 17 per cent of 213 patients (results not reported for the retrospective study). Nine case report/case series reported bleeding complications resulting in death for two patients with increased pro-thrombin time/international normalised ratio. Sixty-four per cent of the patients who experienced bleeding events were at least 70 years of age.

The authors noted that the large percentage of case reports included in the review suggested that there may be publication bias.

Authors' conclusions

There was insufficient consistent evidence to suggest an increased anticoagulant response in patients receiving warfarin and any of the three commonly prescribed fluoroquinolones.

CRD commentary

This review addressed a clear question and was supported by appropriate inclusion criteria. The authors searched relevant databases and efforts were made to identify additional studies by reviewing reference lists of relevant literature. Only two databases were searched for studies published in English, so both language and publication bias could not be ruled out. The authors did not report on the methods used to select studies or to extract data, so reviewer bias and error may have been introduced. The potential influence of publication bias was briefly considered. Study quality was not assessed, but study details were tabulated. Given the variation in study design the authors' decision to combine the studies narratively was appropriate. Given the level of evidence presented, the authors' conclusions were appropriate. However, these should be considered in the context of the methodological weaknesses of the review itself.

Implications of the review for practice and research

Practice: The authors stated that more frequent monitoring of coagulation status would be advisable during concomitant therapy with warfarin and fluoroquinolones.

Research: The authors stated that further confirmation and investigation into possible mechanisms that produce earlier increases in international normalised ratio values for moxifloxacin were needed.

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.